This project evolved from the initial observation of a direct interaction between the gut mucosal homing receptor, integrin alpha4beta7 and the HIV envelope protein gp120. This observation raised new questions related to gp120-mediated signal transduction. HIV and SIV are gut tropic viruses and alpha4beta7-gp120 interactions may shed light on the manner in which HIV impacts the function of immune cells associated with the mucosal immune system. We tested this hypothesis in a NHP model of HIV/SIV infection, and determined that an antibody specific for alpha4beta7 prevented mucosal transmission. We then demonstrated that MAdCAM, the natural ligand of alpha4beta7 delivers a potent costimulatory signal to naive and memory CD4+ T cells following ligation with alpha4beta7. Such costimulation promotes high levels of HIV replication. The anti- alpha4beta7 mAb, that prevented mucosal transmission of SIV, blocks MAdCAM signaling through alpha4beta7 and MAdCAM-dependent viral replication. Subsequently, we demonstrated that the specific affinity of alpha4beta7 for gp120 is similar to its affinity for MAdCAM. We have recently reported that alpha4beta7 binding maps to the V2 loop domain of HIV/SIV gp120. The V2 loop mimics MAdCAM in the way that it binds to alpha4beta7. This mimicry of MAdCAM- a4b7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.